CN105435222A - Recombinant fusion protein preparation - Google Patents
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Abstract
The invention provides a recombinant fusion protein liquid preparation which comprises a recombinant fusion protein, a buffer salt, a stabilizer and a surfactant. The liquid preparation which enables the recombinant fusion protein to be stably stored is established, and can improve physical and chemical stability of the recombinant fusion protein; the liquid preparation can keep the stability of the recombinant fusion protein under conditions of high temperature acceleration, long-term cold storage, repeated freezing and thawing and the like, and can improve the clinical use safety.
Description
Technical field
The present invention relates to biotech drug formulation art, be specifically related to stable recombination fusion protein preparation and its preparation method and application.
Background technology
Age-related macular degeneration (AMD) also known as age-related macular degeneration, for the Aging of macula retinae plot structure changes, the irreversible visual deterioration caused primarily of retinal pigment epithelium and Retinal degeneration or forfeiture.This disease is divided into dryness (atrophic) AMD and moist (exudative) AMD two kinds clinically, and wherein, moist AMD accounts for 20% of the total case load of AMD, and but, in western countries, moist AMD is but the blind first cause of old people.Ophthalmic abnormal angiogenesis is the one of the main reasons that moist AMD occurs and develops, and block the treatment basis that abnormal angiogenesis is moist AMD, it likely slows down the process even stoping disease.VEGF (VEGF) is a kind of secreted protein, and it can bring out angiogenesis, increases vascular permeability, cause inflammation, and these factors is closely related with the development process of moist AMD.Therefore, when developing moist AMD medicine, all VEGF is used as potential therapeutic targets.
Recombinant human vascular endothelial growth factor receptor-antibody-people's complement receptor 1 fusion rotein (hereinafter referred to as IBI302) is exactly the macromolecular drug for AMD disease designing research and development according to above mechanism.It is I kind new medicine with Global Knowledge property right of applicant's autonomous Design, and its route of administration is designed to intravitreal injection, and dosage is expected to be 0.5 ~ 2mg/ eye.
From nineteen eighty-two first reconstituted drug---since human insulin listing, the recombination fusion protein medicine of application protein engineering manufacture is more and more to be developed, wherein part as conventional medication accept by people.But because such medicine is the larger polypeptide of molecular weight or protein, its performance is very unstable, very easily rotten, and easily self aggregation occurs during protein high concentration.These unfavorable factors make this kind of medicine to be made stable, safe and effective preparation and propose huge challenge.
Recombination fusion protein is biomacromolecule, and its structure is very complicated.In production and storage process, can there is various physical and chemical changes in the protein molecular of expression.Physical change has: absorption, unfolding degeneration, gathering and precipitation etc.Chemical change has: deacylated tRNA amine, isomerization, oxidation etc.These changes may have an impact to final products safety and effectiveness.Therefore, a suitable preparation prescription is set up extremely important with the stability and safety that ensure product.
IBI302 is two target spot specific fusion proteins, is national I kind new medicine.Due to the complexity of its structure, cause its unstable chemcial property, albumen easily occurs to assemble and charge isomer is easy to be converted into acidic components from basic component.
Therefore, still needing and research and develop recombiant protein preparation in this area, ensures the stability of product.
Summary of the invention
The object of the present invention is to provide a kind of recombiant protein preparation, can make fusion rotein stable preservation at higher concentrations, in addition, preparation all can keep its stability under the conditions such as high temperature acceleration, Long-term Cold Storage and multigelation, improves Clinical practice safety.
A first aspect of the present invention, provide a kind of recombination fusion protein liquid preparation, described liquid preparation comprises: recombination fusion protein, buffer salt, stabilizing agent, surfactant and sterile water for injection, wherein,
The concentration of described recombination fusion protein is 5 ~ 45mg/mL;
Described buffer salt is one or more the combination in citrate, acetate, and the concentration of described salt is 5-25mmol/L, is preferably 8-22mmol/L;
Described stabilizing agent is one or more the combination in sodium chloride, aminoacid, polyhydric alcohol, described aminoacid is one or more the combination in arginine, glycine, histidine, described polyhydric alcohol is one or more the combination in sucrose, sorbitol, mannitol, and the concentration of described sodium chloride is 100-200mmol/L, described amino acid whose concentration is 50-350mmol/L, the concentration of described polyhydric alcohol is 1 % by weight ~ 15 % by weight, with the total weight of described liquid preparation;
Described surfactant is one or more the combination in polysorbate 20, polyoxyethylene sorbitan monoleate, PLURONICS F87, and the concentration of described surfactant is 0.01 % by weight ~ 0.08 % by weight, with the total weight of described liquid preparation;
And the pH of described liquid preparation is 4.5 ~ 7.5.
In another preference, described recombination fusion protein is Recombinant human vascular endothelial growth factor receptor-antibody-people's complement receptor 1 fusion rotein, and aminoacid sequence is as shown in SEQIDNO.:1 or SEQIDNO.:3.
In another preference, described stabilizing agent is one or more the combination in aminoacid, polyhydric alcohol.
In another preference, the concentration of described sodium chloride is 120-180mmol/L.
In another preference, described amino acid whose concentration is 70-260mmol/L
In another preference, the concentration of described polyhydric alcohol is 3 % by weight ~ 10 % by weight.
In another preference, the concentration of described polyhydric alcohol is 200-300mmol/L, preferably, is 220 ~ 270mmol/L.
In another preference, the pH of described liquid preparation is 5.0-7.2, and preferably, pH is 5.5-7.0.
In another preference, described buffer salt is citrate;
Described aminoacid is arginine;
Described polyhydric alcohol is sucrose;
Described surfactant is polysorbate 20.
In the present invention, described buffer salt is one or more the combination in sodium citrate, sodium acetate.
A second aspect of the present invention, provides a kind of test kit, and described test kit contains the liquid preparation described in first aspect, and the container of liquid preparation described in splendid attire.
Further, also description is contained in described test kit.
A third aspect of the present invention, provides the purposes of the liquid preparation described in first aspect, for the preparation of the medicine preventing and/or treating age-related macular degeneration.
In another preference, described age-related macular degeneration is wet age related macular degeneration.
Liquid preparation of the present invention, can make recombination fusion protein keep stable, make this recombiant protein energy stable existence in prescription, improve the quality of product, extend the shelf life of product, improve Clinical practice safety.Liquid preparation has preferably heat stability, under the conditions such as high temperature acceleration, Long-term Cold Storage and multigelation, all can keep stable.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Detailed description of the invention
Present inventor, through extensively and in depth studying, surprisingly first develops a kind of recombination fusion protein preparation, under the conditions such as acceleration, long-term and freeze thawing, can ensure the stability of product.The applicable recombination fusion protein of the present invention (VEGF inhibitor) also comprises the recombination fusion protein (VEGF inhibitor) that other technique for gene engineerings obtain.On this basis, the present invention is completed.
Recombinant human vascular endothelial growth factor receptor-antibody-people's complement receptor 1 fusion rotein
The preferred recombination fusion protein of the present invention be Recombinant human vascular endothelial growth factor receptor-antibody-people's complement receptor 1 fusion rotein (see US61/629,932 (PCT/US2012/067489); Patent name: Proteininhibitorstocomplementandvegfpathwaysandmethodsof usethereof), aminoacid sequence is as shown in SEQIDNO.:1.
Another preferred recombination fusion protein of the present invention is that the aminoacid sequence of Recombinant human vascular endothelial growth factor receptor-antibody-people's complement receptor 1 fusion rotein is as shown in SEQIDNO.:3.
Liquid preparation
Recombination fusion protein liquid preparation of the present invention, comprises: recombination fusion protein, buffer salt, stabilizing agent, surfactant and sterile water for injection.
In another preference, described liquid preparation, comprises: recombination fusion protein, buffer salt, sodium chloride, surfactant and sterile water for injection.
In another preference, described liquid preparation, comprises: recombination fusion protein, buffer salt, polyhydric alcohol, surfactant and sterile water for injection.
In another preference, described liquid preparation, comprises: recombination fusion protein, buffer salt, aminoacid, surfactant and sterile water for injection.
In another preference, described liquid preparation, comprises: recombination fusion protein, buffer salt, polyhydric alcohol, aminoacid, surfactant and sterile water for injection.
The concentration of described recombination fusion protein is 5 ~ 45mg/mL.
Described buffer salt is one or more the combination in citrate, acetate, and the concentration of described salt is 5-25mmol/L, is preferably 8-22mmol/L.
Described stabilizing agent is one or more the combination in sodium chloride, aminoacid, polyhydric alcohol.
Described aminoacid is one or more the combination in arginine, glycine, histidine.Described amino acid whose concentration is 50-350mmol/L, is preferably 70 ~ 260mmol/L.
Described polyhydric alcohol is one or more the combination in sucrose, sorbitol, mannitol.The concentration of described polyhydric alcohol is 1 % by weight ~ 15 % by weight, is preferably 3 % by weight ~ 10 % by weight.
The concentration of described sodium chloride is 100-200mmol/L.
Described surfactant is one or more the combination in polysorbate 20, polyoxyethylene sorbitan monoleate, PLURONICS F87.
The concentration of described surfactant is 0.01 % by weight ~ 0.08 % by weight, is preferably 0.02 % by weight ~ 0.06 % by weight, with the total weight of described liquid preparation.
The pH of described liquid preparation is 4.5 ~ 7.5, is preferably 5-7.
Liquid preparation of the present invention or comprise the test kit of liquid preparation, may be used for preparing the medicine preventing and/or treating age-related macular degeneration.Recombination fusion protein can keep stable, and product quality is high, long shelf-life, improves Clinical practice safety.
The above-mentioned feature that the present invention mentions, or the feature that embodiment is mentioned can combination in any.All features that this case description discloses can with any composition forms and use, each feature disclosed in description, anyly can be provided identical, alternative characteristics that is impartial or similar object replaces.Therefore apart from special instruction, the feature disclosed is only general example that is impartial or similar features.
Usefulness of the present invention is:
(1) the invention provides the new formulation with the longer shelf-life, recombination fusion protein can be made, as Recombinant human vascular endothelial growth factor receptor-antibody-people's complement receptor 1 fusion rotein keeps stable, preparation all can keep its stability under the conditions such as high temperature acceleration, Long-term Cold Storage and multigelation.
(2) liquid preparation of the present invention, can improve the physical and chemical stability of recombination fusion protein preparation, makes this recombiant protein energy stable existence in prescription, improves the quality of product, extends the shelf life of product, improves Clinical practice safety.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usual conveniently condition is as people such as Sambrook, molecular cloning: laboratory manual (NewYork:ColdSpringHarborLaboratoryPress, 1989) condition described in, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise percentage ratio and number calculate by weight.
Unless otherwise defined, all specialties used in literary composition and scientific words and one skilled in the art the same meaning be familiar with.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.
Universal method
SEC-HPLC method: measure according to the Pharmacopoeia of the People's Republic of China (version in 2010, three) annex III B, detect with hydrophilic silica gels size exclusion chromatograph post, area normalization method calculation sample purity.
Electric charge isomery (cIEF): with coatings capillary pipe NeutralCapillary (50 μm of i.d × 45cm), sample ionization is made at capillary tube two ends making alive by Beckman capillary electrophoresis apparatus (model: PA800plus), ionize rear 32Karat software and analysis integration has been carried out to collection of illustrative plates, calculated by area normalization method.
DSC: use MIcroCalVP-DSC, initial temperature is 10 DEG C, and end temp is 110 DEG C, and sweep speed is 60 DEG C/Hr.Different sample obtains the Tm value of each sample final after deducting corresponding buffer respectively.
Embodiment 1
The impact on fusion rotein stability such as aminoacid, polyhydric alcohol, sodium chloride
Configure various solution according to sterile water for injection table 1 shown, respectively ultrafiltration displacement is carried out to fusion rotein (aminoacid sequence is as shown in SEQIDNO.:3) with each solution prepared.
Be that the corresponding solution dilution of ultrafiltration displacement liquid of 10mg/ml is to 1.5mg/ml by fusion rotein concentration.Then get 1.5ml diluent, and add appropriate polysorbate 20 wherein, make its final concentration be 0.03 % by weight.Use after 0.2 μm of membrane filtration as sample detection.
In addition, each take out solution described in 5ml table 1, add appropriate polysorbate 20 and make its final concentration be 0.03%, then use after 0.2 μm of membrane filtration as buffer blank.Use DSC method, the heat detected under different protein stabiliser melts temperature Tm value, and experimental result is in table 2.
Table 1: variety classes protein stabiliser is to fusion rotein stability influence
2: variety classes protein stabiliser DSC result
Numbering | Tm value (DEG C) | Numbering | Tm value (DEG C) |
1-1 | 57.95 | 2-1 | 53.27 |
1-2 | 58.16 | 2-2 | 53.25 |
1-3 | 58.51 | 2-3 | 57.60 |
1-4 | 58.58 | 2-4 | 58.59 |
1-5 | 57.64 | 2-5 | 52.32 |
1-6 | 58.60 | 2-6 | 58.40 |
1-7 | 58.61 | 2-7 | 57.33 |
The Tm value of each sample final is obtained after 14 groups of different samples are deducted corresponding solution blank respectively.Result of study shows 14 groups of samples and all has higher heat stability.Wherein sample sets 1-1,1-2,1-3,1-4,1-5,1-6,1-7,2-3,2-4,2-6,2-7 heat stability optimum, sample sets 2-1,2-2,2-5 take second place.Result shows, the recombination fusion protein preparation that each component in employing table 1 and recombination fusion protein form has preferably heat stability.
Embodiment 2
PH stability
Prepare the solution of each pH value according to table 3 with sterile water for injection, respectively ultrafiltration displacement is carried out to fusion rotein (aminoacid sequence is as shown in SEQIDNO.:3) with each solution prepared.
Be that the corresponding solution dilution of ultrafiltration displacement liquid of 10mg/ml is to 1.5mg/ml by fusion rotein concentration.Then get 1.5ml diluent and add appropriate polysorbate 20 wherein, making its final concentration be 0.03 % by weight.Use after 0.2 μm of membrane filtration as sample detection.
In addition, each each pH value of 5ml that takes out obtains solution, adds appropriate polysorbate 20 and makes its final concentration be 0.03 % by weight, then uses after 0.2 μm of membrane filtration as buffer blank.Use DSC method, the heat detected under different pH value melts temperature Tm value, and experimental result is in table 4.
Table 3:pH value stabilization embodiment sample
Table 4:pH stability DSC result
Numbering | pH | Tm value (DEG C) |
1 | 5.5 | 59.58 |
2 | 6.0 | 59.89 |
3 | 6.0 | 59.75 |
4 | 6.5 | 59.87 |
5 | 7.0 | 54.85 |
6 | 7.5 | 52.75 |
The Tm value that 6 groups of different samples obtain after deducting corresponding buffer respectively shows, sample 1 ~ 4 has higher heat stability, sample 5 heat stability takes second place, and the Tm of sample 6 is lower slightly, shows that the pH of recombination fusion protein preparation has higher heat stability between 5.5 ~ 7.0.
Embodiment 3
Recombinant human vascular endothelial growth factor receptor-antibody-people's complement receptor 1 fusion protein formulations
By following formulated preparation, fusion rotein aminoacid sequence is as shown in SEQIDNO.:3.
Prescription A
By aseptic subpackaged for semi-finished product in cillin bottle, add a cover rubber stopper and aluminium-plastic cap, obtain finished product.
Prescription B
By aseptic subpackaged for semi-finished product in cillin bottle, add a cover rubber stopper and aluminium-plastic cap, obtain finished product.
Embodiment 4
Accelerated stability is tested
The sample of embodiment 3 is placed in respectively 25 DEG C of calorstats preservations and carries out accelerated stability experiment, after one month, sample taken out and compare with testing result during sample 0 day, to weigh preparation accelerated stability under the high temperature conditions, experimental result as shown in table 5 and table 6.
Show 5:25 DEG C ± 2 DEG C proteic charge isomery result of variations (PI > 8.0)
Sample ID | 0 day | 1 month |
Preparation prescription A (10mg/ml) | 68.75% | 68.87% |
Preparation prescription B (40mg/ml) | 67.82% | 68.45% |
Show 6:25 DEG C ± 2 DEG C purity of protein result of variations (SEC main peak percentage composition)
Sample ID | 0 day | 1 month |
Preparation prescription A (10mg/ml) | 99.23% | 99.01% |
Preparation prescription B (40mg/ml) | 99.03% | 98.51% |
The chemical stability of recombination fusion protein is characterized by capillary isoelectric focusing (cIEF) and purity of protein (SEC-HPLC).Using the change of the percentage composition of iso-electric point > 8.0 and the main peak content of purity of protein (SEC-HPLC) as decision means, result shows: the electric charge isomery content of preparation A, B does not have significant change (see table 5) in acceleration after 1 month.The main peak content of preparation A, B does not have significant change (see table 6) equally simultaneously, and other indexs such as outward appearance, protein concentration, turbidity etc. all significant change do not occur under this acceleration environment.Result shows, under 25 DEG C of acceleration environments, two kinds of preparation prescriptions can keep this recombination fusion protein stability at least 1 month.
Embodiment 5
Long-time stability are tested
In this embodiment, specimen in use is identical with embodiment 4, is preparation prepared by embodiment 3.Sample is placed in respectively 2 ~ 8 DEG C of calorstats to preserve and carry out long-time stability experiment, in three months, six months somes sample is taken out and compare, to weigh preparation long-time stability under cryogenic with testing result during sample 0 day.
Experimental result as shown in Table 7 and 8.
Table 7:2 ~ 8 DEG C proteic charge isomery result of variations (PI > 8.0)
Sample ID | 0 day | 3 months | 6 months |
Preparation prescription A (10mg/ml) | 56.68% | 56.65% | 55.20% |
Preparation prescription B (40mg/ml) | 56.42% | 55.90% | 55.27% |
Table 8:2 ~ 8 DEG C purity of protein result of variations (SEC main peak percentage composition)
Sample ID | 0 day | 3 months | 6 months |
Preparation prescription A (10mg/ml) | 99.23% | 99.32% | 99.09% |
Preparation prescription B (40mg/ml) | 99.03% | 99.09% | 98.64% |
Result shows, under the long-term storage condition of 2 ~ 8 DEG C, sample electric charge isomery (cIEF) and purity of protein (SEC-HPLC) in 6 months do not have significant change.All not there is significant change in other indexs such as outward appearance, protein concentration, turbidity etc. simultaneously under this acceleration environment.Result shows that two kinds of preparations at least can preserve 6 months under long-term conditions.
Embodiment 6
Freeze-thaw stability
This embodiment specimen in use is substantially identical with the pharmaceutical formulation of embodiment 3, and difference is that fusion rotein aminoacid sequence is as shown in SEQIDNO.:1.Thaw at ambient temperature after sample is freezing under ﹣ 80 DEG C of conditions, detect sample after repeating aforesaid operations multigelation 3 times and 6 times, experimental result as shown in Tables 9 and 10.
Table 9: proteic charge isomery result of variations (PI > 8.0) under Freezing-Melting Condition
Sample ID | 0 time | 3 times | 6 times |
Preparation prescription A (10mg/ml) | 56.68% | 60.18% | 60.50% |
Preparation prescription B (40mg/ml) | 56.42% | 62.58% | 60.68% |
Table 10: purity of protein result of variations (SEC main peak percentage composition) under Freezing-Melting Condition
Sample ID | 0 time | 3 times | 6 times |
Preparation prescription A (10mg/ml) | 99.23% | 99.31% | 99.22% |
Preparation prescription B (40mg/ml) | 99.03% | 98.99% | 99.02% |
Result shows, has no significant change after three groups of sample electric charge isomeries (cIEF) and purity of protein (SEC-HPLC) freeze thawing 6 times, and the Testing index such as outward appearance, visible foreign matters that physical characteristic is relevant is all qualified.Result shows that preparation is after at least 6 freeze thawing, and physicochemical properties are still stablized.
Above result of study shows, adopt the liquid preparation that buffer of the present invention and stabilizing agent and recombination fusion protein are mixed with, there is preferably stability, fusion rotein stable preservation at higher concentrations can be made, preparation also all can keep stable under the conditions such as high temperature acceleration, Long-term Cold Storage and multigelation, can improve Clinical practice safety.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (10)
1. a recombination fusion protein liquid preparation, is characterized in that, described liquid preparation comprises: recombination fusion protein, buffer salt, stabilizing agent, surfactant and sterile water for injection, wherein,
The concentration of described recombination fusion protein is 5 ~ 45mg/mL;
Described buffer salt is one or more the combination in citrate, acetate, and the concentration of described salt is 5-25mmol/L, is preferably 8-22mmol/L;
Described stabilizing agent is one or more the combination in sodium chloride, aminoacid, polyhydric alcohol, described aminoacid is one or more the combination in arginine, glycine, histidine, described polyhydric alcohol is one or more the combination in sucrose, sorbitol, mannitol, and the concentration of described sodium chloride is 100-200mmol/L; Described amino acid whose concentration is 50-350mmol/L; The concentration of described polyhydric alcohol is 1 % by weight ~ 15 % by weight, with the total weight of described liquid preparation;
Described surfactant is one or more the combination in polysorbate 20, polyoxyethylene sorbitan monoleate, PLURONICS F87, and the concentration of described surfactant is 0.01 % by weight ~ 0.08 % by weight, with the total weight of described liquid preparation;
And the pH of described liquid preparation is 4.5 ~ 7.5.
2. liquid preparation as claimed in claim 1, it is characterized in that, described recombination fusion protein is Recombinant human vascular endothelial growth factor receptor-antibody-people's complement receptor 1 fusion rotein, and aminoacid sequence is as shown in SEQIDNO.:1 or SEQIDNO.:3.
3. liquid preparation as claimed in claim 1, it is characterized in that, described stabilizing agent is one or more the combination in aminoacid, polyhydric alcohol.
4. liquid preparation as claimed in claim 1, it is characterized in that, the concentration of described sodium chloride is 120-180mmol/L.
5. liquid preparation as claimed in claim 1, it is characterized in that, described amino acid whose concentration is 70-260mmol/L.
6. liquid preparation as claimed in claim 1, it is characterized in that, the concentration of described polyhydric alcohol is 220 ~ 270mmol/L.
7. liquid preparation as claimed in claim 1, it is characterized in that, the pH of described liquid preparation is 5.0-7.2, and preferably, pH is 5.5-7.0.
8. liquid preparation as claimed in claim 1, it is characterized in that, the pH of described liquid preparation is 5.5-7, comprises:
9. a test kit, is characterized in that, described test kit contains the liquid preparation described in any one of claim 1-8, and the container of liquid preparation described in splendid attire.
10. the purposes of the liquid preparation as described in any one of claim 1-8 or test kit according to claim 9, is characterized in that, for the preparation of the medicine preventing and/or treating age-related macular degeneration.
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CN201410497937.4A CN105435222B (en) | 2014-09-25 | 2014-09-25 | Recombination fusion protein preparation |
US15/513,537 US10293045B2 (en) | 2014-09-25 | 2015-09-25 | Stable liquid formulations of recombinant fusion proteins |
EP15845094.0A EP3199179B1 (en) | 2014-09-25 | 2015-09-25 | Recombinant fusion protein formulation |
ES15845094T ES2905614T3 (en) | 2014-09-25 | 2015-09-25 | Recombinant Fusion Protein Formulation |
DK15845094.0T DK3199179T3 (en) | 2014-09-25 | 2015-09-25 | Formulation of recombinant fusion protein |
BR112017006112-0A BR112017006112B1 (en) | 2014-09-25 | 2015-09-25 | RECOMBINANT FUSION PROTEIN FORMULATION |
CA2962480A CA2962480C (en) | 2014-09-25 | 2015-09-25 | Recombinant fusion protein formulation |
AU2015320084A AU2015320084B2 (en) | 2014-09-25 | 2015-09-25 | Recombinant fusion protein formulation |
JP2017526616A JP6196419B1 (en) | 2014-09-25 | 2015-09-25 | Recombinant fusion protein preparation |
PCT/CN2015/090777 WO2016045626A1 (en) | 2014-09-25 | 2015-09-25 | Recombinant fusion protein formulation |
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WO2021129658A1 (en) * | 2019-12-24 | 2021-07-01 | 信达生物制药(苏州)有限公司 | Application of fusion protein in treating age-related macular degeneration |
WO2022017468A1 (en) * | 2020-07-23 | 2022-01-27 | 信达生物制药(苏州)有限公司 | Pd-l1/lag-3 bispecific antibody preparation, and preparation method therefor and use thereof |
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EP3713591A1 (en) * | 2017-11-20 | 2020-09-30 | Just-Evotec Biologics, Inc. | Aflibercept formulations containing a lysine salt as tonicifying agent and uses thereof |
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UA127771C2 (en) * | 2018-11-09 | 2023-12-27 | Джянгсу Хенгруй Медісін Ко., Лтд. | TGF-β RECEPTOR FUSION PROTEIN PHARMACEUTICAL COMPOSITION AND USE THEREOF |
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AU2015320084A1 (en) | 2017-04-20 |
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EP3199179B1 (en) | 2021-12-01 |
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